Comparison of neoadjuvant immunotherapy plus chemotherapy versus chemotherapy alone for patients with locally advanced esophageal squamous cell carcinoma: A propensity score matching.

Objectives: Clinical studies on immune checkpoint inhibitors (ICIs) combined with neoadjuvant chemotherapy (nCT) have been carried out for the resectable esophageal squamous cell carcinoma (ESCC). So far, few studies have compared the survival outcomes of nCT plus ICIs and nCT alone. This study aimed to compare the efficacy and safety of neoadjuvant ICIs combined with nCT versus nCT followed by esophagectomy for patients with resectable locally advanced ESCC. Methods: A retrospective analysis of ESCC patients underwent nCT or nCT combined with ICIs followed by esophagectomy (from March 2013 to April 2021) was performed. A 1:1 propensity score matching (PSM) with a caliper 0.01 was conducted to balance potential bias. Results: A total of 47 comparable pairs of ESCC patients receiving nCT and nCT combined with ICIs were selected for the final analysis. The tumor regression grade (TRG) 0 and pathologic complete response (pCR) rates in the nCT+ICIs group were significantly higher than those of the nCT group (21.7% vs. 4.5%, P=0.016; and 17.0% vs. 2.1%, P=0.035, respectively). The rate of nerve invasion was 4.3% in the nCT+ICIs group, significantly lower than 23.4% of the nCT group (P=0.007). The incidences of adverse events in the nCT+ICIs group were similar compared with the nCT group and there was no grade 5 toxicity in either group. The 1-, 2-year disease-free survival rates (DFS) were 95.7%, 80.7% and 76.1%, 63.8% in the two groups (P=0.001, and P=0.046, respectively). The 1-year OS was improved in the nCT+ICIs group, which was close to a statistical difference (95.7% vs. 84.8%, P=0.074). Local recurrence rate in the nCT+ICIs group was 6.4%, significantly lower than 21.3% of the nCT group (P=0.036), while there was no significant difference in the distant metastasis. Conclusions: Compared with nCT alone, neoadjuvant immunotherapy plus nCT for patients with locally advanced ESCC has an advantage in pathological response, and could improve DFS with a good safety and feasibility, while long term survival validation is still needed further.

Are People With Blood Group O More Susceptible to Nasopharyngeal Carcinoma and Have Worse Survival Rates? A Systematic Review and Meta-Analysis.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a common malignant tumour in Southeast Asia, especially in southern China. ABO blood groups have been proven to play an important role in many cancers. However, it is still controversial whether the ABO blood group has a definite relationship to susceptibility to NPC and the prognosis of NPC patients. This meta-analysis was performed to elucidate the correlation between ABO blood group and NPC to provide more data for clinical practice. METHODS: A systematic search was performed of the Chinese National Knowledge Infrastructure (CNKI), Wanfang, Web of Science, EMBASE, and PubMed databases up to December 31, 2020. Stata 11.0 statistical software was used for this meta-analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 studies including 6938 patients with NPC were selected. Blood group O was relevant to Chinese NPC patients, and patients with blood group O had a significantly lower incidence of NPC, while blood group A had no correlation with susceptibility to NPC. There was no difference in the 3-year overall survival (OS), locoregional relapse-free survival (LRRFS) or distant metastasis-free survival (DMFS) rates between patients with blood group O and those with non-O blood groups; worse 5-year OS, LRRFS and DMFS rates were found in patients with blood group O, whereas blood group A was not related to prognosis. CONCLUSION: Blood group O in Chinese patients with NPC seems to be a protective factor for morbidity. However, once patients with blood group O are diagnosed with NPC, this blood group often indicates unfavourable OS, LRRFS and DMFS rates. It is recommended that more attention should be paid to the influence of blood group factor on patients in the treatment of NPC.

Comparison of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy for esophageal cancer: a meta-analysis.

Aim: To compare the clinical efficacy of neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) for esophageal cancer. Methods: Randomized controlled trials reporting on the comparison of nCRT and nCT for esophageal cancer were identified. Results: Three eligible randomized controlled trials were identified and included with a total of 375 patients (189 nCRT, 186 nCT). Outcomes showed that compared with nCT group, R0 resection and pathologic complete response (pCR) rates were significantly increased in nCRT group. However, no significant difference was seen in 3- and 5-year progression-free survival or 3- and 5-year overall survival. Conclusion: The addition of radiotherapy to neoadjuvant chemotherapy results in higher R0 resection rate and pCR rate, without significantly impacting survival.

Comparison of elective nodal irradiation and involved-field irradiation in esophageal squamous cell carcinoma: a meta-analysis.

It remains controversial whether radical radiotherapy in patients with esophageal squamous cell carcinoma (ESCC) still requires elective nodal irradiation (ENI), or only involved-field irradiation (IFI). In this study, a meta-analysis was conducted to compare ENI and IFI in the treatment of ESCC, in order to provide guidance for clinical practice. Literature on the use of ENI and IFI in the treatment of ESCC was retrieved, and the last access date was 31 December 2017. A meta-analysis was performed to evaluate the relative advantages and disadvantages of using ENI and IFI. Ten studies, involving a total of 1348 patients, were included in this analysis; of these, 605 patients underwent radiotherapy only, and 743 underwent radiochemotherapy. There was no significant difference in the 1-, 2- or 3-year local control rates between ENI and IFI, or in the 1-, 2- or 3-year overall survival rates. However, the incidences of ≥Grade 3 acute esophagitis and pneumonia were significantly lower in the IFI group. There were no differences in the rates of ≥Grade 3 myelosuppression or of out-field recurrence or metastasis between these two groups. Thus, neither local control rates nor overall survival rates differed significantly between the ENI and IFI groups, but in the latter group, incidences of severe radiation esophagitis and pneumonia were significantly lower. IFI was not associated with an increase in out-field recurrence or metastasis.

Expression of hypoxia inducible factor 1 alpha and its clinical significance in esophageal carcinoma: A meta-analysis.

Many studies have analyzed the relationship between hypoxia inducible factor 1 alpha expression and its relation to differentiation, lymph node metastasis, and other clinicopathological variables of esophageal carcinoma, but the results are still inconsistent. This meta-analysis was carried out to explore hypoxia inducible factor 1 alpha in esophageal carcinoma and its correlation with clinicopathological features and prognosis, in order to provide comprehensive reference for clinic. A total of 18 studies including 1566 patients with esophageal squamous cell carcinoma were enrolled. The results showed that compared with para-carcinoma tissue, the expression of hypoxia inducible factor 1 alpha was significantly enhanced (odds ratio = 0.122, 95% confidence interval = 0.074-0.201, p = 0.000); hypoxia inducible factor 1 alpha was associated with differentiation (odds ratio = 1.458, 95% confidence interval = 1.108-1.920, p = 0.007), T classification (odds ratio = 0.457, 95% confidence interval = 0.265-0.786, p = 0.005), lymph node metastasis (odds ratio = 0.337, 95% confidence interval = 0.185-0.614, p = 0.000), and pathological tumor-node-metastasis stage (odds ratio = 0.362, 95% confidence interval = 0.177-0.740, p = 0.005), whereas there was no relation to histological grade, lymphatic vessel invasion, blood vessel invasion, 3- to 5-year overall survival and disease-free survival. Patients with hypoxia inducible factor 1 alpha overexpression had poor differentiation, increased depth of tumor invasion, more lymph node metastasis, and late pathological tumor-node-metastasis stage. Hypoxia inducible factor 1 alpha could be an indicator for differentiation, T classification, lymph node metastasis, and pathological tumor-node-metastasis stage, and it is worth further study.

Relationship between EGFR over-expression and clinicopathologic characteristics in squamous cell carcinoma of the esophagus: a meta-analysis.

Over-expression of epidermal growth factor receptor (EGFR) has been identified as a common feature associated with clinical outcome in many types of cancer, including squamous cell carcinoma of the oesophagus (SCCO). However, the clinical importance of EGFR over-expression in SCCO remains unsettled as conflicting results exist. Therefore we carried out the present meta-analysis of published studies for clarification. A total of 13 studies including 1,150 patients were enrolled. EGFR over-expression was positive in 722 of these cases. With EGFR over-expression, patients had higher depth of invasion, vascular invasion, and poor prognosis. However, expression had no relation with degree of differentiation, histological grade, lymph node metastasis, clinical stage or lymphatic invasion. EGFR over-expression is probably a valuable predictor for the T stage, vascular invasion and OS, and it could be used as a poor prognosis indicator for the esophageal SCC patients. Targeting therapy to EFGR should be considered to the combined treatment in SCCO.

Interactions between filamin A and MMP-9 regulate proliferation and invasion in renal cell carcinoma.

This study aimed to analyze the expression, clinical significance of filamin A (FLNA) in renal cell carcinoma (RCC) and biological effects in a cell line by regulating FLNA expression. Immunohistochemistry and Western blotting were used to analyze FLNA protein expression in 70 cases of RCC and normal tissues to study the relationship with clinical factors. FLNA lentiviral and empty vectors were transfected into RCC to study the influence of up-regulated expression of FLNA. FLNA siRNA was transiently transfected into ACHN kidney carcinoma cells by a liposome-mediated method and protein was detected by Western blotting. The level of expression was found to be significantly lower in RCC than normal tissues (p<0.05). No correlation was noted with gender, age, tumor size or pathological types (p>0.05), but links with lymph node metastasis, clinic stage and histological grade were noted (p<0.05). Loss of FLNA expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (p<0.05). Results for biological function showed that ACHN cells transfected with FLNA had a lower survival fraction, significant decrease in migration and invasion, higher cell apoptosis, higher percentage of the G0/G1 phases, and lower MMP-9 protein expression compared with ACHN cells untransfected with FLNA (p<0.05). However, renal 786-0 cells transfected with FLNA siRNA had a higher survival fraction, significant increase in migration and invasion, and higher MMP-9 protein expression compared (p<0.05). In conclusion, FLNA expression was decreased in RCC and correlated significantly with lymph node metastasis, clinic stage, histological grade and poor overall survival, suggesting that FLNA may play important roles as a a tumor suppressor in RCC by promoting degradation of MMP-9.

Characteristics of recurrence after radical esophagectomy with two-field lymph node dissection for thoracic esophageal cancer.

Postoperative radiotherapy has shown positive efficacy in lowering the recurrence rate and improving the survival rate in cases involving lymph node (LN) metastasis. However, the radiotherapy target volume remains controversial. Certain published studies have paid more attention to LNs found to be affected during surgery, while little effort has been made to study the LN metastatic pattern following surgery and its influence on the determination of the target volume of postoperative radiotherapy. In this study, the locoregional recurrence of esophageal squamous cell cancer was examined in 134 patients receiving radical surgery with two-field lymph node dissection from 2004 to 2009. In the 134 cases of recurrence, LN metastasis occurred in 126 patients (94.0%) while 13 patients (9.7%) developed anastomotic recurrence and 5 patients (3.7%) experienced tumor bed recurrence. The difference among the groups was statistically significant (P= 0.000). In the 126 cases with lymph node metastasis, the mediastinal metastasis rate (80.2%) was significantly higher compared with the rate of supraclavicular metastasis and abdominal metastasis (P= 0.000). A significant difference was identified between right and left supraclavicular LN metastasis (31.7% vs 16.7%, P= 0.005). Furthermore, the difference between the metastatic rates in the upper (73.8%), middle (39.7%) and lower mediastinum (1.6%) was statistically significant (P=0.000). Nevertheless, no significant correlation between the rate of LN metastasis was observed in the supraclavicular, mediastinal and abdominal regions for upper, middle and lower thoracic carcinomas (P= 0.404, P= 0.718 and P= 0.169, respectively). Based on our data, LN metastasis is the major locoregional recurrence pattern for esophageal squamous cell cancer following radical surgery. The high-risk lymphatic drainage areas include the supraclavicular nodes, recurrent laryngeal nerve nodes, azygos nodes and subcarinal nodes.

HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression.

Hypoxia-inducible factor-1α (HIF-1α) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF-1α in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1α, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1α on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1α, E-cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1α protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF-1α mRNA showed no significant change. SiRNA could block HIF-1α effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1α was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1α inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line.

[Effect of HIF-1α and its mechanism on invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo].

AIM: To investigate the effects of HIF-1α by RNAi on invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo, in order to explore its probable mechanism. METHODS: CoCl(2); was used to mimic tumor hypoxic microenvironment. mRNA and protein levels of HIF-1α, E-cadherin and MMP-2 under hypoxia were detected by RT-PCR and immunohistochemistry. The effects of silencing HIF-1α by RNAi on HIF-1α, E-cadherin and MMP-2 mRNA were detected by RT-PCR. The effect of RNAi on invasion and metastasis were tested by cell scratch assay and transwell chambers. The Eca109-implanted nude mouse model was established, and the effects of HIF-1αon tumor growth and lymphoid node metastasis were observed. The expressions of HIF-1α, E-cadherin and MMP-2 in transplanted tumors were detected by Western blot, and the effects of HIF-1α on tumor growth, invasion and metastasis in vitro and in vivo were analyzed. RESULTS: Hypoxia up-regulated HIF-1α protein, mRNA and protein levels of E-cadherin down-regulated, and MMP-2 up-regulated, while had no effect on HIF-1α mRNA . RNAi could silencing HIF-1α effectively, and inhibited E-cadherin or MMP-2 decreased or increased, respectively. The migration and the number of invading cells decreased (P<0.05) after silencing HIF-1α by RNAi. The tumor volume was much smaller, lymph node metastasis rate lower as well in vivo (P<0.05). CONCLUSION: Via its effects on E-cadherin and MMP-2, HIF-1α regulate the growth, invasion and metastasis of Eca109 cells in vitro and in vivo.

[Bidirectional effect of MnSOD overexpression on the proliferation of esophageal cancer cells in vitro].

OBJECTIVE: To construct a recombinant lentiviral vector for manganese superoxide dismutase (MnSOD) gene expression, and observe its effect on the proliferation of esophageal cancer cells in vitro. METHODS: Chemical methods were employed for synthesis of the MnSOD cDNA sequence sections, along with the attB sites. Target gene fragment was constructed on the pMD-18T vector, and the recombinant plasmid pDONR221 was obtained after BP recombination reaction. Sequencing was followed by LR recombination reaction between the plasmid and DEST to obtain the lentiviral vector, which worked with helper plasmid for co-transfection of human embryonic kidney epithelial cells (293T cells). Amplification was done to determine its titer, and both transfection and selection procedures were made to get two stable transfected esophageal cancer TE-1 cell lines with medium MnSOD expression (TE-1Mm cells) and high MnSOD expression (TE-1Mh cell), and empty vector cell (TE-1Mn cells). Reverse transcription polymerase chine reaction (RT-PCR), immunofluorescence, immunocytochemistry and Western blot were used to detect the target gene with respect to its expression in the TE-1 cells. Additionally, colorimetric 3-[4,5-dimethy thiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, agar colony formation assay, annexin V-FITC/PI staining and flow cytometry experiments were also conducted as to observe the influence of the medium and high MnSOD overexpressions on the proliferation of esophageal cancer cells. RESULTS: RT-PCR indicated that the transfected TE-1 cells showed positive MnSOD expression at different levels. Immunofluorescence, immunocytochemistry and Western blot suggested that TE-1Mm cells and TE-1Mh cells had MnSOD protein expression at different levels. MTT assay indicated that TE-1Mm cells had a significantly decreased survival rate compared with that of the two control cells (TE-1 cells and TE-1Mn cells), and TE-1 Mh cells had an significantly increased survival rate (P<0.05). The colony formation ability of TE-1Mm cells was (23.0 +/- 2.7)%, and that of TE-1Mh cells was (45.3 +/- 4.5)%, significantly different form the (34.7 +/- 4.2)% in TE-1 cells and (33.7 +/- 4.7)% in TE-1Mn cells (P<0.05). Annexin V-FITC/PI double staining experiment of the stably transfected cells cultured for 48 h showed that the early apoptosis rate in TE-1Mm cells was (10.6 +/- 1.0)%, significantly higher than (2.6 +/- 0.2)% in the TE-1 cells, (2.5 +/- 0.6)% in the empty vector cells and (1.0 +/- 0.1)% in the TE-1Mh cels (P<0.05). The fluorescence index (FI) of mitochondrial apoptosis of TE-1Mm cells was 0.948 +/- 0.019, significantly lower than that of TE-1 cell (1.000 +/- 0.022) and empty vector The fluorescence index of TE-1Mn cells (0.997 +/- 0.023) and TE-1 cells (1.000 +/- 0.022) were significant different from that of 0.948 +/- 0.019 in TE-1Mm cells and 1.076 +/- 0.022 in TE-1Mh cells, indicating a significant difference of mitochondrial apoptosis between the cell groups. FCM results indicated that the ROS fluorescence index of TE-1Mm cells was 0.859 +/- 0.040, that of TE-1Mh cells was 0.763 +/- 0.039, significantly lower than that of TE-1 cells (1.000 +/- 0. 042) and empty vector cells (1.002 +/- 0.047) (P<0.05). CONCLUSIONS: Stably transfected cell lines with MnSOD expression have been successfully established. MnSOD overexpression shows bidirectional effect on the proliferation of esophageal cancer cells.